4. Estrogens and progestins
• Estrogens and progestins are hormones that produce many
physiological actions
• In women,
– Developmental effects (estrogens are largely responsible
for pubertal changes in girls and secondary sexual
characteristics)
– Neuroendocrine actions involved in: Control of ovulation
and the preparation of the reproductive tract for
fertilization and implantation
– Major Actions on: Minerals, Carbohydrates, Proteins, and
Lipid Metabolism
• In men, effects:
– Bone
– Spermatogenesis
– Behavior
5. NEUROHORMONAL
CONTROL OF FEMALE
REPRODUCTIVE SYSTEM
Sex steroids are involved
in the regulation of the
cyclic changes
expressed in the
menstrual cycle, and are
important in pregnancy.
6.
7. Estrogens
• Estrogens are primary female sex hormones, the steroid
compounds, named for their importance in the estrous cycle
• estrus/oistros (period of fertility for female mammals) +
gen/gonos = to generate.
• Natural estrogens-
– Estradiol, Estriol, Estrone
• Synthetic estrogens-
– Steroidal Ethinylestradiol, Mestranol, Tibolone
– Non-steroidal Diethylstilbestrol, Hexestrol,
Fosfestrol
8. Natural estrogens
Estrone (E1)
17 (beta)-estradiol (E2)- most potent
Estriol (E3)
• Estradiol is primarily produced by theca and granulosa cells of the ovary,
and is the predominant form in premenopausal women.
• Estrone is formed from estradiol in a reversible reaction. This is the
predominant form of circulating estrogen after menopause.
• Estriol is the estrogen the placenta secretes during pregnancy.
12. Estrogens --M/A
Estrogens (steroidal agents)
-bind to nuclear receptors in target cells-causes dimerization of receptors
-regulate protein synthesis via Estrogen Response Elements [EREs] of target
genes
-gene transcription (via coactivator proteins)
-produce effect
Antagonist- binds to receptor- interacts with corepressor proteins-
inhibits gene transcription.
Both ERs expressed in most tissues (predominance seen)
ERa –uterus, vagina, breast, hypothalamus, BVs, Bone
ERb - prostate glands (m) & ovaries (f)
13. Estrogens --P/A
Sex organs
• Cause pubertal growth in females-uterus, fallopian tubes, &
vagina.
• Proliferation of endometrium in pre-ovulatory phase.
• In absence of progesterone (anovulatory cycles) withdrawal of
estrogen alone produces menstruation.
• In modest doses estrogen causes delay in menstruation. (Oral
contraceptive pills are used to postpone the menstruation onset)
• It increases rhythmic contractions of the fallopian tubes and
uterus, and induces a watery alkaline secretion from the
cervix-favorable to sperm penetration.
• They also sensitize uterus to oxytocin.
14. Estrogens --P/A
Secondary sex characters
At puberty causes growth of breasts-proliferation of ducts and
stroma, fat accumulation, pubic and axillary hairs, feminine
body outline and behavior changes.
Acne is commonly seen, due to small amount of androgen
produced simultaneously, estrogen administration causes
regression of acne.
15. Estrogens --P/A
Metabolic effects
• Estrogens are anabolics, albeit weaker than testosterone.
• Continued action promotes fusion of epiphyses.
• It promotes positive calcium balance, partly by inducing
renal hydroxylase enzyme which generates active form of Vit
D3.
• Mild salt and water retention, treated with diuretics.
16. Estrogen and Osteoporosis
• Estrogen deficiency is associated with large increases in bone
resorption caused by increased osteoclast (OC) numbers (due
to enhanced OC formation and reduced OC apoptosis) and by
increased OC activity, resulting in osteoporosis in post
menopausal women.
• Estrogen upregulates TGF-β (Transforming growth factor beta), an
inhibitor of bone resorption that acts directly on OC to
decrease activity and increase apoptosis.
17. Estrogens –P/A
• Incresead BP after prolonged use.
• High doses of estrogens and progestins may precipitate
diabetes or impair its control.
• Estrogens decrease plasma LDL cholesterol while HDL and
triglyceride levels are raised. [premenopausal women-
atherosclerosis rare]
• Blood coagulability is increased due to induction of
synthesis of clotting factors (factors II, VII, IX and X).
• They increase lithogenicity of bile by increasing cholesterol
secretion & reducing bile salt secretion.
18. Estrogens –C/U
• Contraceptives
• Acne – Topical with antimicrobials, isotretinoin
Dysmenorrhoea- PG synthesis inhibitors 1st line drugs,
Estrogens given in severe cases (decrease PG
synthesis in endometrium)
• Hormone replacement therapy (HRT) in postmenopausal
women.
– Reversing the menopausal symptoms
– Preventing osteoporosis and fractures
– Reducing CAD, MI and stroke.
19. Estrogens –C/U
• Atrophic/Senile vaginitis- often in conjunction with
antibacterial.
• Delayed puberty in girls- cyclic therapy or start with low dose
gradually attain full replacement dose.
• Dysfunctional uterine bleeding- estrogens given as an
adjuvant to progestins
• Prostate carcinoma- palliative care, high doses needed;
Fosfestrol preferred (Pro drug of diethylstilbestrol)
20. Estrogens –A/E
• Suppression of libido, gynaecomastia and feminization when
given to males.
• Fusion of epiphyses and reduction of adult stature when given
to children.
• Stilbestrol given to pregnant women, especially during first
trimester increased the incidence of vaginal and cervical
carcinoma in the female offspring in childhood or early
adulthood. From about 1940 to 1971, DES was given to pregnant women
in the mistaken belief it would reduce the risk of pregnancy complications
and losses.
21. Estrogens –A/E
• Estrogens can increase the growth of existing
breast cancer, but low-dose estrogen HRT -no
such effects.
• Long-term estrogen therapy doubles
incidence of gallstones.
• May worsen migraine, epilepsy and
endometriosis.
• Deep vein thrombosis risk increased 2-3 times.
22. Antiestrogens and SERMs
• Nonsteroidal antiestrogens
– Clomiphene citrate
– Fulvestrant
They have antagonistic and agonistic actions
depending upon species and target organ.
SERMS- Selective estrogen receptor modulators
Tamoxifen citrate
Raloxifene
Ormeloxifene
Bind to ERs and interacts with different coactivators
and corepressors in a tissue specific manner
23. Anti-estrogens and SERMs
Anti-estrogens
– Pure antagonists
– Clomiphene is for
treatment of infertility
in anovulatory women
– Fulvestrant is used for
the treatment of
breast cancer
Selective Estrogen Receptor
Modulators (SERMs)
– Compounds with tissue-
selective actions
– The goal of these drugs is to
produce beneficial estrogenic
actions in certain tissues (ex.
Brain, bone, liver) during
postmenopausal hormone
therapy
– Tamoxifen, Raloxifen,
Toremifine
24. Clomiphene citrate
• In humans acts as pure estrogen antagonist binding to both
ERa and ERb.
• It blocks estrogen feedback inhibition of pituitary and thus
induces Gn secretion. The amount of LH/FSH released at each
secretory pulse is increased. In response, the ovaries enlarge
and ovulation occurs if the ovaries are responsive to Gn.
• Antagonism of peripheral actions of estrogen results in hot
flushes.
25. Clomiphene citrate
C/U
• Sterility due to failure of ovulation.
• As an aid for in-vitro fertilization (synchronous maturation of
ova) test tube baby
• Oligospermia in males -promotes spermatogenesis and
testosterone secretion.
A/E
Polycystic ovaries, Multiple pregnancy,
Hot flushes, Gastric upset,
Vertigo, Allergic dermatitis.
26. Tamoxifen citrate
• Potent estrogen antagonist in breast carcinoma cells, blood
vessels and at some peripheral sites, and partial agonist in
uterus, bone, liver and pituitary.
• Estrogenic action
– Decrease in total and LDL cholesterol without any change in HDL and
triglyceride level.
– Stimulation of endometrial proliferation.
– Lowering of Gn and prolactin levels in postmenopausal women
– Improvement of bone density
• Antiestrogenic action
– Inhibition of human breast cancer cells and hot flushes
27. Tamoxifen citrate
• Treatment of breast cancer in both pre- and post-menopausal women,
though aromatase inhibitors are gaining popularity.
• It is also effective following the surgery in cancer of male breast (60-70 yr).
• Improvement in bone mass due to anti-resorptive effect, and in lipid profile
too.
• T/o male infertility- as alternative to clomiphene.
A/E
• Hot flushes, vomiting
• Vaginal bleeding, vaginal discharge, menstrual irregularities
• Increased risk of venous thromboembolism, mild leucopenia
• Dermatitis, anorexia, depression,
30. Progestins M/A
• Progesterone receptor (PR) is confined mostly to female genital
tract, breast, CNS and pituitary.
• Analogous to ER, upon binding the hormone PR undergo
dimerization, attaches to progesterone response element
(PRE) of target genes and regulate transcription through
coactivators.
• The anti-progestins also bind to PR, but the conformation
assumed is different from agonist bound receptors and
opposite effects are produced by interaction with corepressors.
• PR exists as PR-A short and PR-B long isoforms.
31. Progestins P/A
• The main function of progesterone is preparation of the uterus
for embryo implantation and maintenance of pregnancy.
Uterus
Progesterone brings about secretory changes in the estrogen
primed endometrium; hyperemia, tortuocity of glands and
increased secretion occurs while epithelial proliferation is
suppressed.
Vagina
Progesterone induces pregnancy like changes in the vaginal
mucosa-leukocyte infiltration of cornified epithelium.
32. Progestins P/A
Cervix
Progesterone converts the watery cervical secretion induced by
estrogens to viscid, scanty and cellular secretion which is hostile to
sperm penetration.
Breast
Progesterone causes proliferation of acini in the mammary glands.
Continuous exposure during pregnancy halts mitotic activity and
stabilizes mammary cells. Acting in concert with estrogens, it
prepares breast for lactation.
CNS
Sedation (high conc. in pregnancy)
33. Progestins P/A
Respiration
Stimuates respiration (high dose, pregnancy)
Body temperature
Slight rise 0.5deg C. Higher body temp during luteal phase.
Metabolism
Impaired glucose tolerance [long term use]
Progestins, especially those with androgenic activity (19-
nortestosterone derivatives) tend to raise LDL and lower HDL
levels.
Pituitary
Progesterone is a weak inhibitor of Gn secretion from pituitary. It
decreases frequency of LH pulse, but increases amount of LH
secreted per pulse.
34. Progestins C/U
• Contraceptive
• HRT- in conjunction with estrogen to decrease risk of inducing
endometrial carcinoma.
• Dysfunctional uterine bleeding (large doses)
A progestin with inherent estrogenic action is preferred.
Endometriosis
Continued administration of progestins induces an
anovulatory, hypoestrogenic state by suppressing Gn
release. The direct action on endometrium prevents bleeding
in the ectopic sites by suppressing menstruation. GnRH
agonists and antiprogestins may be used.
35. Progestins C/U
Premenstrual syndrome/tension
Fluoxetine and other SSRIs preferred. If severe,
premenstrual syndrome requires suppression of ovulation by
combined estrogen-progesterone treatment given cyclically.
Threatened/habitual abortion
A pure progestin without estrogenic or androgenic activity
used. Allylestrenol is preferred
Endometrial carcinoma
Progestins are palliative in about 50% cases of advanced/
metastatic endometrial carcinoma.
36. Progestins A/E
Higher doses
Breast engorgement, headache, rise in body temperature,
edema, esophageal reflux, acne and mood swings
Continuous dosing--Amenorrhoea, or irregular bleeding
Long term use increase risk of breast cancer
Blood sugar may rise and diabetes may be precipitated
(Levonorgestrel-potent)
Painful IM injections
In early pregnancy can cause masculinization of female fetus
and other congenital abnormalities.
37. ANTIPROGESTIN
Mifeprostone
• It is a potent anti-progestational, significant
antiglucocorticoid as well as antiandrogenic activity.
• Follicular phase- causes attenuation of midcycle Gn
surge from pituitary- delay in ovulation
• Luteal phase- prevents secretory changes of
progesterone
• Later in the cycle, it blocks progesterone support to the
endometrium, unrestrains PG release from it- this
stimulates uterine contractions. It also sensitizes the
myometrium to PGs and induces menstruation.
38. ANTIPROGESTIN--C/U
• Termination of pregnancy-Upto 7 weeks 600 mg single dose
complete abortion.
• Cervical ripening: 24-30 hours before attempting surgical
abortion or induction of labour
• Postcoital contraceptive- within 72 hrs
• Once-a-month contraceptive: not much used
• Induction of labour : Couteracting progesterones uterine
relaxant action
• Cushing’s syndrome: Palliative support in inoperable cases
40. Cyclic hormone therapy
• Estrogen is taken in pill or patch form for 25
days, with progestin added somewhere
between days 10 - 14. The estrogen and
progestin are used together for the remainder
of the 25 days. Then, no hormones are taken
for 3 - 5 days. There may be monthly bleeding
with cyclic therapy.
• Cyclic hormone therapy is often recommended
when a woman is starting menopause.
41. AROMATASE INHIBITORS
• Letrozole, Anastrozole and Exemesta
• Aromatization of 'A' ring of testosterone and
androstenedione is the final and key step in the production of
estrogens (estradiol/estrone) in the body.
42. In-vitro fertilization
• Louis brown 1978
• Robert G. Edwards, the physiologist who
developed the treatment, was awarded
the Nobel Prize in Physiology or Medicine in
2010.
